Benzodiazepines Drug of the Month: download
Transcript and Sources
What exactly is it? Where does it come from in nature? How is it turned into useable form? How is it consumed?
Now it’s time for our drug of the month, where we bring you an intro, science, history, and recent trends in a different drug each month. We skipped last week since there are 5 Sundays in May, but that means this week is the first installment of May’s drug, which is actually more a category of drugs: benzodiazepines, also known as benzos, and including certain well-known brands such as Xanax and Valium.
As I said, benzodiazepine is not an individual drug, but rather a class of drugs, and what they have in common is the core chemical structure that includes a benzene ring and a diazepine ring. Benzos are classified as depressants, and are most often prescribed for things like anxiety and many different sleep disorders.
If you’re like me and don’t have a degree in chemistry, you’re probably wondering, what exactly is a benzene or diazepine ring? As it sounds, these are groups of atoms connected to one another in a ring shape, which can then be connected to other rings or groups of atoms in order to form very complex molecules. Benzene is a specific compound with the formula C6H6, with the molecule being composed of 6 carbon atoms in a ring, with one hydrogen atoms attached to each, looking kind of like spokes when using the ball and stick model of visualizing atoms. Diazepine is a little more complicated, because it has a few different configurations, but all of those are made up of 5 carbons, two nitrogens, and 6 hydrogens, arranged in different ways but always in a ring.
So to sum that up, benzodiazepines have no set chemical structure because there are so many of them, but to look at two examples: Valium, which is a brand name for the compound diazepam, has the chemical formula C16H13ClN2O, while Xanax, the brand name of alprazolam, has the formula C17H13ClN4. As you can see, benzos always have carbon, hydrogen, and nitrogen, but can also include oxygen and other atoms.
Like LSD and some of the other drugs we’ve talked about, benzodiazepines are completely synthetic and can only be made in a lab setting, never being found in nature. Of course, all of the ingredients have to come from somewhere, so there are some natural roots: benzene is actually a natural part of crude oil, making it a petrochemical, so it’s created through that long, natural process of turning organic matter into oil over millions of years. Scientists can then extract the benzene from crude oil, combine it with the other constituents, and create whatever specific benzodiazepine they’re working on.
All of these look like a white powder, which is then typically put into capsules or pressed into tablets, and administered orally. This may be familiar to people who have a Valium or Xanax prescription, or who have used them off-label for recreational or self-medicating purposes. Some types of benzos, such as Valium, Ativan, and Librium can also be dispensed intravenously, while another, under the brand name Versed, is only done through IV. This is typically seen in hospital settings when someone with a serious medical condition or injury needs assistance relaxing or sleeping.
That’s all for the introduction to benzodiazepines, but there’s much more coming next week, where we’ll dive into the science of benzos: how they interact with the body, their medical effects, and some of their potential side effects.
What is the science behind how it interacts with the body? What receptors does it influence? What are the medical effects of it, potential side effects?
Now it’s time for the drug of the month, where we give an overview and dive into the science, history, and current events of a different drug each month. For May we’re focusing in on benzodiazepines, also known as benzos, and for this second installment, I’ll be going into the science of benzos: how they interact with the body, their desired effects, and some of their possible side effects too.
As I explained last week, benzodiazepines aren’t a single drug, but rather, a class of drugs with similar chemical structures and effects, two of the most well-known being diazepam under the brand name Valium, and alprazolam under the brand name Xanax. While different benzodiazepines will behave differently, they are all depressants and have effects that are similar enough to tackle all at once, since there is so much overlap and breaking them down into individual drugs of the month would probably get a little tedious.
As I also explained in the last episode, benzos are most often taken orally, either as a capsule or a pressed pill. Xanax come in long, thing pills referred to as “Xanax bars,” which contain 2mg of alprazolam and are scored so that users can easily break them into halves or fourths depending on their needs. Whether benzos are taken orally or through an IV, the way they work is by increasing the efficiency of GABA, an acronym for gamma-Aminobutyric acid. GABA is the chief inhibitory neurotransmitter in the central nervous system, meaning it reduces the activity of your neurons. So, when benzodiazepines increase the efficiency of GABA, that means it gets better at inhibiting neurons from firing, which produces a stable, calming effect.
Of course, while all benzos create similar effects, they also all have some differences. Since they are metabolized into different compounds, they can have varying speeds of onset and biological half-lives, and the two aren’t necessarily related – some benzos come on quickly and leave your body quickly, while others can come on quickly and stay in your body for quite some time. The same goes for benzodiazepines that take a while to feel their effect. For example, diazepam has a fast onset but a long biological half-life of 20 to 80 hours, while midazolam, which also comes on quickly, only has a half-life of 1.5 to 2.5 hours. Alprazolam has an intermediate speed of onset and a half-life of 12-15 hours. These varying characteristics make it possible for doctors to choose a benzodiazepine that is right for the patient’s needs, as a shorter-acting benzo could be better for quick relief of insomnia, while a longer-acting benzo may be a better choice for keeping anxiety at bay throughout the day.
While different benzos are better for different things, as a class, they are prescribed for a wide range of conditions that can be improved using a depressant. For example, they’re often used for anxiety, including specific conditions like generalized anxiety disorder or social anxiety disorder, and can also help people who are susceptible to panic attacks. Benzos are also widely used for insomnia, as they can slow down a racing mind and make it easier for people to rest, but for this use they are typically recommended for only short amounts of time, as they bring on sleep but reduce its quality, so long-term use can actually lead to less overall rest. Another, even shorter-term use of benzodiazepines is for treating convulsive seizures, as they can be strong anti-convulsives, so doctors will use fast-acting benzos, typically injected, to stop a seizure in its tracks.
Benzodiazepines are also often used for people without any conditions, but who are undergoing surgery, with doctors giving them the drug a few hours before the procedure. This not only helps reduce anxiety about the procedure and all the tenseness that comes with it, but the right dose of benzos can also cause amnesia, so that patients don’t remember the scary parts of the surgery once it’s over. For example, I’ve known people who were given Xanax before getting LASIK surgery, a particularly scary procedure since you need to be awake and it involves your eyes.
Another interesting use case for benzos is in the management of alcohol withdrawal, partly because it’s another depressant that can lightly sedate the patient while the withdrawal symptoms run their course, but also because in extreme cases of heavy alcohol use, withdrawal can actually cause delirium and seizures, which benzos can treat. This is just one of many examples of how consuming one drug can actually be very helpful in quitting another drug, which anti-drug campaigners often claim is impossible.
Of course, like all drugs, all benzodiazepines do come with risks. While benzos have a much smaller risk of overdose than other depressants, they do still have some. For Alprazolam, the LD-50 in rats it 1220 mg/kg, and for diazepam there’s more of a risk, with an LD-50 in rats of 249 mg/kg. But for some perspective, each of these are hundreds of time the normal dose, so overdose is incredibly rare except when benzos are used in combination with alcohol, opiates, or other depressants, which dramatically increase the risk of overdose.
Building a tolerance to benzodiazepines is also a common problem, leading to fewer therapeutic effects and worsening withdrawals, which also occur. In addition to withdrawals, abruptly stopping using benzos can also lead to a rebound, which is the return of the original symptom, such as anxiety or insomnia, but worse than before you started taking the drug. Because of this, doctors will usually have patients wean off their regimen rather than stopping suddenly, so anyone using without a doctor should also avoid taking them too frequently for too long and then stopping abruptly.
So that’s all for the science of benzodiazepines, and we’ll be back next week with a look into the history of this widely used class of drugs.
When did people start using it? Who uses it now? How have the laws and societal attitudes about it evolved over time?
And now it’s time for drug of the Month, where we take a closer look at a different drug each month. For May, we’ve been talking about benzodiazepenes, commonly known as benzos, and last week, Sam went over the science behind benzos and how they interact with the human body. On today’s episode, we’ll be learning about the History of Benzodiazepines.
As Sam explained previously, benzos are a class of drugs with similar chemical structures none of which exist in nature, and that can only be created in a lab setting.
The first benzodiazepine to be synthesized was chlordiazepoxide (marketed under the name “Librium”), in 1955 by Leo Sternbach, a Croatian-born Polish American chemist, who was working on the development of tranquilizers at Hoffmann–La Roche, a Swiss pharmaceutical company that still produces Valium today. Hoffman-LaRoche is also famous for being the first company to mass-produce synthetic Vitamin C. As with so many other common synthetic substances, the pharmacological properties of the compounds prepared by Sternbach were initially disappointing, and Sternbach abandoned the project. But two years later, in April 1957, his colleague Earl Reeder noticed a “nicely crystalline” compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach’s focus on other issues. But, upon re-discovery, the researchers submitted the compound for a standard battery of animal tests, expecting the pharmacology results to be negative and hoping to publish the chemistry-related findings. However, the compound showed very strong sedative, anti-convulsant, and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium.
Sternbach went on to synthesize a number of other benzodiazepines including diazepam, known as Valium; clonazepam, known as Klonopin; and flunitrazepam, known as Rohypnol. Yes, Rohypnol, also known as “roofies” or “the date rape drug” are also benzos.
The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, which are another type of depressant, but which have a higher risk for overdose, and by the 1970s benzos had largely replaced the older drugs in routine medical practice, such as for the treatment of anxiety and insomnia. A study from the 1970s showed, however, that approximately 1 in 4 prescriptions for benzos were actually for the treatment of purely physical symptoms, such as sporting injuries or other minor muscle pains, despite the lack of clear evidence that there was any therapeutic efficacy. In 1977, benzodiazepines were the most prescribed medications in the world.
The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. It was estimated that about 10% of patients who started on benzos in general practice were still using the drug six months later.
According to a 1992 article in the British Journal of General Practice, titled “Is there still a role for benzodiazepines in general practice?,” the percentage of people attempting to stop taking the drugs or reducing their dosage and who reported symptoms of withdrawal was between 30% and 100%, depending on the definition used. Studies during that era demonstrated some success in assisting long term users to withdraw from benzos, replacing the drug with counseling, support, and relaxation therapy. However, in a truly encouraging moment, the article goes on to warn general practitioners against forcing withdrawal where it may not address the underlying cause of the dependence. The author writes, “While many patients may indeed be psychologically dependent on benzodiazepines, such dependence does not justify the judgment that they are abusing the drugs. Patients who remain as long-term users may not all benefit from withdrawal and if pressured to withdraw may simply resort to other psychotropic substances, legal or illegal, some of which are more damaging to physical and psychological health.”
The article also notes that the level of public concern and media coverage around benzos as a “social problem” in the UK may have increased the rate of self-reported dependence. In contrast, in Germany, where there was significantly less media coverage, only 2% of patients reported difficulties with withdrawal symptoms.
That same year however, in 1992, benzos were the subject of the largest-ever personal injury class-action lawsuit in British history, involving 14,000 patients represented by 1,800 law firms, alleging that drug manufacturers knew of the dependence potential but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal.
In the United States, benzos are currently classified as Schedule IV controlled substances, which means they are deemed to have a low potential for abuse, that they have currently accepted medical use in the United States, and that any abuse may lead only to limited physical or psychological dependence. Flunitrazepam, or Rohypnol, is subject to more stringent regulations in certain states.
That’s all for this week’s segment of Drug of the Month, where we talked about the history of benzodiazepines. Tune in next week, when Sam will be back to discuss news and trends surrounding the drug.
How have usage rates changed recently? How has the law changed? What is the modern culture like? News items?
Now it’s time for the drug of the month, where we dive into an overview, the science, history, and recent trends in a different drug each month. For May, we’ve been talking about benzodiazepines, a class of drugs that includes brand names like Xanax and Valium. For this, the fourth and final installment, I’ll be going into some current events around benzos: new research about their effects, changes in the medical community’s approach to them, usage rates, and changes in the illicit market and the culture surrounding benzos.
As we talked about in the science installment two weeks ago, benzodiazepines are frequently prescribed for treating general anxiety, insomnia, and a range of other conditions that require the patient to relax, since it is a depressant. While they were first introduced to the market in the 1950s, benzos have been growing in popularity over the past few decades. From 1996 to 2013, the latest year in which data is available, the percentage of adults filling a benzo prescription increased by about 37%, from 4.1% to 5.6%. There was a more striking increase in the quantity of benzos prescribed for each patient, going from 1.1 kilograms per 100,000 adults to 3.6, an increase of 327%, so those modest increase in patient size was combined with each patient consuming a lot more. However, more recently, there has also been a movement in the medical community to use benzodiazepines more sparingly, with one example being that many doctors are now first prescribing less dangerous drugs like trazedone for insomnia instead of going straight to benzos.
Part of the reason for this growing movement for reducing benzodiazepine prescriptions is due to their connection to the overdose epidemic. While most reporting has focusing on opioid overdoses, which are responsible for the majority of overdose deaths, benzos also do play a part. In fact, benzodiazepines were present in 31% of the 22,000 fatal overdoses in 2013. This doesn’t mean that all of those people overdosed on benzos alone, as it’s much more common for overdoses to be caused by a combination of drugs. As depressants, benzodiazepines are very dangerous when used in combination with other depressants like opiates or alcohol, which can act as a multiplier in their effect and danger, slowing the respiratory system to the point of ceasing function. A study published in February 2016 found that the risk of consuming opiates in combination with benzos is approximately four times greater than the risk of consuming opiates alone.
Because of this increased risk, there is also a movement among doctors to better educate their peers about this, and for the government to take action to do so. In February, a group of 41 officials from state and municipal health departments petitioned the FDA to add warnings to both opiate and benzodiazepine labels explaining the increased risk of using them in combination. The FDA acknowledged the petition and said they’re examining the issue, but has not yet mandated such warnings.
There have also been some big trends in the non-medical, or at least off-label, use of benzos in recent years. It appears that the drug-using community, as reflected in forums like reddit’s r/Drugs, largely view benzos as a dangerous drug that has high potential for addiction and generally should not be messed with, though there is a small but vocal group of people who support their recreational use in moderation. It does not face quite the same stigma as heroin or other opiates, but there does appear to be more stigma than marijuana, psychedelics, or other drugs with lower or zero risk of addiction and overdose.
Of course, there are also some terrible off-label uses of benzodiazepines. As Rachelle explained last week, Rohypnol, commonly referred to as “roofies” and a widely known date-rape drug, is a benzodiazepine, so benzos are an important part of the ongoing conversation about rape culture, particularly on college campuses. A May 2016 study in the journal Psychology of Violence surveyed over 6,000 students at three colleges and found that 1 in 13 students reported being drugged or suspecting that they were drugged at some point. 79% of these respondents were female. However, it must also be noted the benzos are not the only substance used to drug people’s drinks — for example, GHB, short for gamma-Hydroxybutyric acid and also widely associated with date rape, is not a benzodiazepine.
Finally, the popularity of so-called “legal highs” has also brought benzodiazepines into the spotlight, but incorrectly. One very popular legal high sold at convenience stores and online calls itself Benzo Fury, and while many have assumed “benzo” was short for benzodiazepine, in this case it is actually short for 1-benzofuran-6-ylpropan-2-amine, referred to as simply 6-APB. So the “benzo” in benzo fury is a reference to benzofuran, not benzodiazepines – they share part of their name because both of them have a benzene ring, but benzofuran is lacking the diazepine ring. Like many unregulated drugs supposedly not intended for human consumption, various packages of Benzo Fury could have varying potency or even varying chemical components, with little or no labels indicating what’s inside. While 6-APB has stimulant and hallucinogenic effects somewhat similar to MDMA, users who don’t know exactly what, or how much, they’re putting in their bodies have led to some high-profile deaths and injuries. So when you hear about Benzo Fury, keep in mind that it’s a different kind of benzo.
But that brings us to the end of the fourth and final installment of May’s drug of the month, or rather, class of drugs, benzodiazepines. Next month, we’ll be shifting away from synthetics and back to the plant-based drugs with four installments on Ayahuasca.